Compounds of the perhydrochrysene series and preparation thereof



United States Patent COMPOUNDS OF THE PERHYDROCHRYSENE SERIES ANDPREPARATION THEREOF Raymond 0. Clinton, North Greenbush Township,Rensselaer County, N. Y., assignor to Sterling Drug Inc., New York, N.Y., a corporation of Delaware No Drawing. Application October 18, 1954Serial No. 463,055

16 Claims. (Cl. 260-488) This invention relates to new compounds of theperhydrochrysene series (D-homosteroids) and to processes for theirpreparation. More particularly the invention relates to compounds havingthe formula wherein X=, X: and X": are selected from the classconsisting of 0=, H and H OH OAcyl R is selected from the classconsisting of H, OH and OAcyl; and R is selected from the classconsisting of H, OH, OAcyl and halogen. The invention also contemplatescompounds corresponding to the above structure I having a double bond inthe 17,17a-position formed by elimination of RH; likewise the compoundshaving a halogen atom in the 4-position, X being 0.

The compounds of the above formula I wherein X: is 0 R is OH or OAcyland a double bond is present in the 4,5-position possess corticalhormone-like activity, and the compounds within the scope of Formula Iare intermediates for the preparation of said compounds having corticalhormone-like activity. Some of said intermediates also possessbiological activity per se, for example, as antagonists of progesteroneor testosterone. Methods for the preparation of said intermediates andconversion of the latter into the biologically active compounds aredescribed hereinbelow.

In the above general Formula I, the groups X, X and X" can be the sameor different, and R and R can be the same or different.

In compounds of Formula I where OAcyl groups are present, the nature ofsuch acyl groups is not critical as they are used only as a blocking orprotecting means for the hydroxy groups. The preferred types of acylgroups are those derived from carboxylic acids of relatively lowmolecular weight, i. e., containing from one to about eight carbonatoms, including inter alia lower-alkanoic acids, lower-aliphaticdicarboxylic acids, and monocyclic aromatic carboxylic acids optionallysubstituted by one or more inert groups such as nitro, alkyl, alkoxy andhalogen groups. Thus Acyl can be low'er-alkanoyl, such as formyl [HCO],acetyl [CH CO-], propionyl [C H C0-], butyryl [CH (CH CO], isobutyryl[(CH CHCO], valeryl [CH (CH CO], caproyl [CH (CH CO-], octanoyl [CH (CHCO] and the like; carboxy-lower-alkanoyl, such as succinyl [HOOCCH CHCO] glutaryl [HOOC(CH CO] adipyl [HOOC(CH CO] and the like; andmonocarbocyclic aroyl, such as benzoyl [C H CO], p-toluyl [p -CH C HC0], p-nitrobenzoyl [p-O NC H CO] and the like.

When the group R in Formula I stands for halogen it can be any one ofthree halogens, chlorine, bromine and iodine. Bromine is a preferredhalogen.

In compounds wherein ring D is saturated, the group R at the17a-p0sition can be in either the aor fi-configuration, the side chainR'CH C(=X") then assuming either the B- or a-configuration,respectively. Acyloxy or hydroxy groups in the 3- and ll-positions canalso be in either the ocor fl-configuration.

The compounds of the invention are prepared by a series oftransformations as outlined in the following flow sheet. In theformulas, X=, and R have the same meanings as given above. R" stands foreither a hydrogen atom or an acyl group, and Hal stands for CH3 CH3 XlXI- CH3 C 3 VIII IX CH3 CH3 CHaHal C H2O R" C=O =0 R CH2 CH3 $11101?(FHQORW C 0 0 R I... XI:

CH3 CH O- O: I

Hal

XII XIII The starting materials of Formula II are prepared as describedin my copending U. S. application, Serial No. 384,325, filed October 5,1953, and now abandoned, and in my copending U. S. application, SerialNo. 475,810, filed December 16, 1954, now Patent No. 2,822,382, which isa continuation-in-part of said application, Serial No. 384,325.

Compounds of Formula III are prepared from compounds of Formula II byreactions resulting in hydration of the ethynyl group at thel7a-position, i. e., conversion of the ethynyl group to an acetyl group.The conversion II III is carried out by heating II either with aceticanhydride, mercuric ion and boron trifluoride followed by hydrolysis, orwith aniline, mercuric ion and Water. The same transformation can alsobe effected by treating a compound of Formula II with an N-bromo amideor imide such as N-bromoacetamide under conditions whichproducehypobrornous acid in situ, thus converting the 17a-ethinyl groupto a l7a-dibromoacetyl group. The latter is then debrominated by heatingwith zinc to give a compound of Formula III.

Compounds of Formula II are converted to compounds of Formula IV byreacting II where R is hydrogen with boron trifluoride in ethyleneglycol in the presence of mercuric ion. Dehydration is eifectedproducing a double bond in the 17,17a-position. Compounds IV can then becatalytically hydrogenated to produce a compound of Formula V, analogousto compounds of Formula III but lacking the 17-OR group. In thecatalytic hydrogenation of compounds of Formula IV, the hydrogen atomentering at the 17a-position preferentially takes the a-position,leaving the acetyl group in the B-position. Accordingly, it is possibleto convert a compound of Formula II where the ethynyl group is orientedin the a-position to a compound of Formula V wherein the acetyl group isin the fl-position, thus, in effect, pro ducing an inversion at 17a.

The compounds of Formula V where X is L RI! can be converted tocompounds of Formula VI by formation of the 20-enol acylate by heatingwith an acid anhydride in the presence of a strong acid, reacting theresulting 17a(20)-unsaturated compound with a peroxidic compound such ashydrogen peroxide or a peracid, e. g. peracetic or perbenzoic acid togive the corresponding 17a(20)-oxide of the 20-enol acylate, and finallysaponifying the latter with a base which hydrolyzes the oxide ring togive a l7aa-hydroxy group in a compound of Formula VI.

The compounds of Formula VI are a subgroup of compounds of Formula IIIwhere X is In these compounds the 20-keto group can be reduced to a20-hydroxy group by means of alkali metals or alkali metal derivativesto give a compound of Formula VII. Such reducing agents include lithium,sodium or potassium in loWer-alkanols or ammonia, alkali metal hydrides,alkali metal borohydrides and alkali metal aluminum hydrides. Catalytichydrogenation can also be employed if desired. If an ll-keto group ispresent in the compounds of Formula VI (X is 0) it will also be reducedto an ll-hydroxy group LOH) by the above-named reagents, although theZO-keto group can be selectively reduced by mild treatment with sodiumborohydride without aifecting the ll-keto group.

The compounds of Formula VII can be converted to compounds of Formula VX is H LOR by heating VII, preferably in the form of its ZO-acylate,with zinc dust. Elimination of the elements of water or carboxylic acidoccurs, the 17-hydroxy group is lost, and the 20-keto compound V isproduced. In the course of the reaction the stereochemical orientationof the side chain at 17a is inverted. For example, if the CH CH(OH)group at 17a in compound VII is in the a-configuration, it will beconverted to compound V with the CH CO group in the B-configuration, andvice versa.

Compounds of Formula VIII, corresponding to III or V where X is can behalogenated in the 2l-position to give compounds of Formula IX. This isaccomplished by reacting thecompound VIII with a halogen selected fromchlorine, brornine and iodine or with a compound which acts as a sourceof one of these halogens. Bromination is generally preferred and can becarried out by contacting the compound VIII withelementary bromine in aninert solvent such as chloroform or acetic acid, or With compoundscontaining available positive bromine, such as pyridinium bromideperbromide. Iodination can be accomplished by reacting the ZO-ketocompound with iodine and an epoxide according to Buck and Clinton U. S.Pat. 2,678,932. Chlorination can be accomplished by reacting theZO-ketdcompound with sulfuryl chloride according to Johnson and ClintonU. S. Pat. 2,686,188. In compounds of Formula VIII where X is O, theZI-position only is halogenated, be cause the positions adjacent to an11-keto group (positions 9 and 12) are relatively unreactive.

The hydroxyl functionin the 3-position of a compound of Formula IX isthen oxidized 'to 'a keto group by the action of oxidizing agents suchas chromic oxide, N-

bromoacetamide or an aluminum alkoxide (Oppenauer method) thus producinga compound of Formula X. In compounds where X is the ll-hydroxy groupcan also be oxidized to an ll-keto group (X'=O), however the ll-hydroxygroup is less readily attacked than the 3-hydroxy group, and the lattercan be oxidized selectively under controlled conditions Withoutatfecting the ll-hydroxy group.

The compounds of Formula X can then be reacted with an alkali metalacylate to replace the 21-bromine by an acyloxy group, forming compoundsof Formula XI. The over-all conversion of IX to XI need not take placein the order given; the replacement of the 21-bromine by acyloxy mayprecede the oxidation of the S-hydroxy group if desired.

The introduction of a double bond in the 4,5-position is eiiected byhalogenation of a compound of Formula XI in the 4-position by proceduresanalogous to those described above for halogenation in the 21-position,followed by dehydrohalogenation of a compound of Formula XII thus formedto give an unsaturated ketone of Formula XIII. The dehydrohalogenationis brought about by heating the 4-halo compound with a basic substance,e. g., an amine, hydrazine or a substituted hydrazine, or with certainnon-basic dehydrohalogenating agents such as anhydrous lithium chloride.

It is, of course, possible to oxidize the 3-hydroxy group of a compoundof Formula VIII, halogenate at the 4- position and dehydrohalogenate toproduce a compound analogous to structure XIII but having hydrogen inplace of the OR group in the 2l-position.

Hydroxy or keto groups at positions 3 and 11 can be readilyinterconverted by conventional methods known to oxidize cycloaliphatichydroxy groups to keto groups, e. g., with hexavalent chromium,N-bromoamides, aluminum alkoxides (Oppenauer method), etc.; or to reducecycloaliphatic keto groups to hydroxy groups, e. g., with lithiumaluminum hydride, sodium borohydride, the Meerwein-Pondorfi? method,etc. Selective conversion can often be effected by taking advantage ofthe different reactivities of groups in the 3-, 11- and ZO-positions, orby protecting one group by means of acylation in the case of hydroxygroups or ketal formation in the case of keto groups.

Hydroxy groups present in the molecule can be readily acylated toprepare any desired ester by reacting the free hydroxy compound with anacid, acid anhydride or acid halide according to conventionalprocedures.

The following examples will further illustrate the invention, but thelatter is not restricted thereto.

Example 1 3a acetoxy D homopregnan 17a;8 ol 11,20-

dione [111; X is -OCOCHa X is O, R isH].-17aa-ethynyl-D-homoetiocholane- 3a,17a/8-diol-11-one, M. P.220.5-228 C. (II; X is OH, X is O, R is H) (5.0 g.), and 2.5 g. ofmercuric oxide were dissolved in 100 ml. of glacial acetic acid bywarming. The solution was cooled to C., 30 ml. of 90-95% aceticanhydride was added, followed by 2 ml. of 47% boron trifluoride-ethercomplex. .The reaction mixture was kept at room temperature (33-34 C.)for about twenty-four hours, and then added to 300 ml. of cracked ice.The mixture was made basic with 35% sodium hydroxide solution. The solidmaterial was collected by filtration, washed with water and dried at 50C. The total solid product was refluxed with g. of potassium carbonatein 400 ml. of methanol and 40 ml. of water for one and one-half hours.The insoluble inorganic matter was removed by filtration,

the filtrate concentrated to a small volume, diluted with water, and thesolid material which separated was collected by filtration, washed anddried, giving 5.0 g. of crude D-homopregnane-3a,17a/3-diol-11,20-dione,M. P. 120-137 C. The latter was mixed with 40 ml. of -95% aceticanhydride and 20 ml. of pyridine and the mixture was heated for one houron a steam bath. The mixture was then added to ice-water, allowed tostand until the excess acetic anhydride had been hydrolyzed, and theacetylated product was extracted with methylene dichloride. The,methylene dichloride extracts were washed with dilute hydrochloric acidand dilute sodium carbonate solution, dried over anhydrous sodiumsulfate and concentrated. The residue was dissolved in 80 ml. of ether,the solution diluted to 800 ml. with petroleum ether (Skellysolve A),and the resulting solution was chromatographed on a column of 200 g. ofchromatographic grade silicon dioxide. The column was eluted withether-petroleum ether (Skellysolve A) mixtures of gradually increasingether content; 50% ether brought out crystalline material which wascollected and recrystallized from an ethyl acetatepetroleum ether(Skellysolve C) mixture, and dried at 70 C., giving 1.5 g. of3u-acetoxy-D-h-omopregnanl7ap-ol-1L20-dione, M. P. 189-193" C. A samplewhen recrystallized twice from a small volume of methanol and dried atC. in vacuo for eight hours had the M. P. 196.5199.5 C. (corn), [a]=+54.0 (1% in chloroform).

Analysis.Calcd. for C I-1 0 C, 71.25; H, 8.97. Found: C, 71.02; H, 8.80.

Example 2 30 acetoxy D homopregnan 1711a 0l 11,20- dione IIII; X is --OCO CH:

X is O, R" is H] was prepared from 5.0 g. of 172118-ethynyl-D-homoetiocholan-3a,17aa-diol-1l-one, M. P. 260.5-266 C., 2.5 g.of mercuric oxide, 20 ml. of acetic anhydride and 2 ml. of 47% borontrifluoride-ether complex according to the manipulative proceduredescribed above in Example 1. The total crude product after hydrolysisand acetylation (5.5 g.) was boiled with 30 ml. of ethyl acetate andfiltered, removing 0.5 g. of insoluble material. The filtrate wasconcentrated and the residue chromatographed as described above inExample 1. The desired material was eluated with an ether-petroleumether (Skellysolve A) mixture containing 40% of ether, and wasrecrystallized successively from an ethyl acetate-petroleum ether(Skellysolve C) mixture, a minimum amount of ethanol, and twice from abenzene-petroleum ether (Skellysolve C) mixture, and dried at 110 C. invacuo for seven hours, giving 3aacetoxy-D-homopregnan-17aa-ol 11,20dione, M. P. 2105-2125 C. (corn), [a] =+31.1 (1% in chloroform).

Analysis.-Calcd. for C H O C, 71.25; H, 8.97. Found: C, 71.47; H, 8.80.

Example 3 allowed to stand for one-half hour and then filtered. Thefiltrate-was concentrated'in vacuo to a 30-40 m1. volume, 1.5 liters ofwater "was added and the solid material-was collected by filtration. Thelatter product was dissolved in 300 m1. of methanol containing 20 g. ofpotassium carbonate and 50 ml. of water, and the solution wasrefluxedfor one and one-half hours. The solution was'concentrated invacuo, the solid material was collected by' filtration, washed withwater and dried at'70 C., giving 11.57 g. ofD-homopregnane-3a,17aadiol-11,20-dione. The latter was mixed with 40 ml.of acetic anhydride and 20 ml. of pyridine and the mixture was heatedfor one-half hour on a steam bath, and then added to 1.5 liters ofwater, kept for one hour, and the solid product collected by filtration.The 12.4 g. 'of material thus obtained was recrystallized from an ethylacetate-petroleum ether (Skellysolve C) mixture, using activatedcharcoal for decolorizing purposes, and then recrystallized frommethanol and dried at 70 C., giving 7.2 g. of3a-acetoxy-D-homopregnan-17aa-ol 11,20-dione, M. P. 209210 C. (uncorr.).

Example 4 (a) 3,17a/3 cliacetoxy 17am ethynyl D homoetiocholan-l 1-0ne[11; X is V -oooorn X is O, R is CH CO].-A mixture of 40.0 g. of17amethynylrDhomoetiocholane-3a,l7af3-diol-ll-one, 300 ml. of 90-95%acetic anhydride, 45 g. of p-toluenesulfonic acid monohydrate and 500ml. of acetic acid was kept for four days at room temperature. Thereaction mixture'was then added to 12 liters of water, allowed to standfor 1.5 hours, and the solid product was collected by filtration, driedat 70 C., recrystallized first from an ethyl acetate-petroleum ether(Skellysolve C) mixture, then from methanol, and again from ethylacetatepetroleum ether, giving 412 g. of 3a,17a,8-diacetoxy-17awethynyl-D-homoetiocholan-1l-one, M. P. 203- 204 C., followed 'byresolidification and again melting at 215 216C. A pure sample of thecompound had the M. P. 205.5207.5 C. with resolidification and remeltingat 2145-2175 C. (corr.), [a] =+5.6 (1% in chloroform).

Analysis.Calcd. for C H O C, 72.86; H, 8.47. Found: C, 72.71; H, 8.19.

' Similarly starting from 2.0 g. of17afl-ethynyl-D-homoetiocholane-Zia,17aor-diol-1l-one there was preparedthe s'tereoisomeric 300,179.0c diacetoxy 17aB ethynyl D-homoetiocholan-ll-one', M. P. 204.5205.5 C.,

(1% in chloroform v 'Analysis.-Calcd. for C H O C, 72.86; H, 8.47.Found: C, 72.64; H, 8.34.

(b) D-homopregnane-iaJ7afi-di0l-IL20-di0ne [111; X is X "is'O, R is'H].-A mixture of 37.43 g. of 3a,17aB-diacetoxy-l7aa-ethynyl-D-homoetiocholan-1l-one, 52.1 g. of mercuricchloride, 11.16 ml. of aniline, 636 ml. of henzene and 187 ml. of waterwas refluxed with stirring for twenty-four hours. The reaction mixturewas concentrated in vacuo to dryness and the residue was dissolved in750 ml. of absolute ethanol. To the solution was added ml. ofconcentrated ammonium hydroxide, and hydrogen sulfide gas was passedthrough at 70 C. for one-half hour. The mixture was filtered while warmand concentrated invacuo-to about 500 ml. To the solution was added 25ml. of concentrated hydrochloric acid and 50 mhof water and the solutionwas refluxed for two hours, allowed to stand for about fifteen hours,and then 8 50 ml. of 35% sodium hydroxide solution was added and themixture refluxed for one and one-half hours. Water (150 ml.) was added,the ethanol was removed in vacuo, the residue diluted with water and thesolid material (35.7 g.) collected by filtration and recrystallized fromethyl acetate, giving 26.0 g. of D-liomopregnane-h,17afl-diol-11,20-dione, M. P. 224225 C. (uncorr.).

In another experiment the intermediate 30:,17 a'S-diacetoxy-D-homopregnaue-l1,20-dione [111; X is X is O, R is CH CO]was isolated, M. P. 167-168.5 C. (corr.), [a] =+20.6 (1% in chloroform.)when recrystallized from methanol.

Analysis.Calcd. for C H O C, 69.93; H, 8.58. Found: C, 69.72; H, 8.80.

Example 5 (a) 21,21 dibromo 30,17dfidiacetoxy-D-homopregnane-11,2-0-dione.A solution was prepared from 4.286g. of 3or,17afi-diacetoxy-17au-ethynyl-D-homoetiocholaull-one in 200 ml.of tertiary-butyl alcohol containing 10 ml. of glacial acetic acid. Asecond solution was prepared from 5.12 g. of 97% N-bromoacetamide and5.14 g. of sodium acetate trihydrate in 50 ml. of water. The twosolutions were then mixed and allowed to stand at room temperature (28C.) for nineteen hours. The reaction mixture Was concentrated in vacuoto a 50 ml. volume, diluted to 50 ml. with water, and the solid materialwhich formed was collected by filtration and dried at 70 (1., giving5.749 g. of 21,21-dibromo-3m,17aB-diacetoxy-D-homopregnane-l1,20-dione,M. P. 177-188 C.

(b) 3 11,1 7afl-diacet0xy-D-h0mopregnane-1 1,20-'di0ne. A mixture of3.00 g. of 21,21-dibromo-3'a,17a5-diacetoxy-D-homopregnane-l1,20-dione,obtained as describ d above in part (a), 5 g. of zinc dust, 5 g. ofsodium acetate trihydrate and 40 ml. of acetic acid was heated to C.,shaken vigorously for fifteen minutes and filtered while warm. Theresidual zinc was washed with acetic acid, the washings combined withthe filtrate, and the filtrate diluted to 800 ml. with water. The solidproduct was collected by filtration and dried at 70 C., giving 2.28 g.of 3a,17ap-diacetoxy-D-homopregnane-11,20-dione, M. P. 154-157 C.

Example 6 D-hoinopregnane-Socl7aa-di0l-1L20-di0ne [111; X is ---0H X isO, R" is H] was prepared by hydrolysis of the corresponding S-acetate(Examples 2 and 3) by heating with a dilute methanolic solution ofpotassium carbonate. The methanol was removed in vacuo, the residuediluted with water, and the solid material was collected by filtration,dried, recrystallized first from an ethyl acetatepetroleum ether(Skellysolve C) mixture and then from ethyl acetate and dried at C. invacuo for eight hours, giving D-homopregnane-3a,17aor-diol-11,20-dione,M. P. 184-186 C. (corr.), [a] =0 (1% in chloroform).

Analysis-Calcd. for C H O C, 72.89; H, 9.45. Found: C, 72.95; H, 9.55.

Example 7 D-homopregnanedogl7a 3-diol-lL20-dione [111; X is X is O, R"is H] was prepared from the corresponding 3-acetate (Example 1) or the3,17a-diacetate (Example 4) by heating with a dilute methanolic solutionof potassium carbonate. The methanol was removed in vacuo,

the residue diluted with water, and the solid which separated wascollected by filtration, recrystallized from ethyl acetate and dried at110 C. in vacuo for eight hours, givingD-homopregnane-3u,l7a/3-diol-11,20-dione, M. P. 225226.5 C. (corr.), [a]=+28.2 (1% in chloroform).

Analysis.-Calcd. for C H O C, 72.89; H, 9.45. Found: C, 72.85; H, 9.69.

D-homopregnane-3u,17a,8-diol-11,20-dione was found to possessprogesterone antagonizing properties determined as follows: female ratsseven days pregnant were castrated and given a standard dose ofprogesterone. Varying doses of the new compound were injected and thesize of the embryos and placentas subsequently measured. The retardeddevelopment of the latter as compared with those of control animals wasindicative of progesterone-antagonizing properties in the new compound.

3ot-propionoxy D homopregnan-17a/3-ol-11,20-dione,3a-hexanoyloxy-D-homopregnan-17afi-ol-11,20-dione, 3atrimethylacetoxy Dhomopregnan-Uafl-ohl1,20-dione, 3 a-(/8'carboxypropionoxy)-D-homopregnan- 1 'lafi-ol- 1 1,20- dione, 30cbenzoyloxy-D-homopregnan-l7a,8-ol-11,20-dione, and3a-(fi-cyclopentylpropionoxy)-D-homopregnan- 17a 8-ol-11,20-dione can beprepared by reacting D-homopregnane-3a,l7a,B-diol-1l,20-dione withpropionic anhydride, caproyl chloride, trimethylacetyl chloride,succinic anhydride, benzoyl chloride, and fl-cyclopentylpropionylchloride, respectively, in the presence of pyridine.3aformoxy-D-homopregnan-17afi-ol-11,20-dione can be prepared by reactingD-homopregnane-3a,17afl-diol-11,20- dione with formic acid in thepresence of acetic anhydride. The 17a-hydroxy group can also be acylatedunder forcing conditions, for example, in the presence ofp-toluenesulfonic acid.

Example 8 D-homopregnan-I7aB-0l-3,1I,20-zri0ne [III; X and X are 0, R isH].-About 3.3 g. of D-homopregnane-3a, 17aa-diol-1l,20-dione in 25 m1.of acetone was cooled to C., and 4 ml. of water and 2 g. ofN-bromoacetamide were added. The mixture was kept at 5 C. for fourhours, then poured into 500 ml. of water, mixed well, and the solidmaterial was collected by filtration and dried at 50 C. giving 1.0 g.,M. P. l96l99 C. The latter was recrystallized twice from an ethylacetate-petroleum ether (Skellysolve C) mixture and dried at 120 C. invacuo for eight hours, giving D-homopregnan-17am-ol-3,11,20- trione, M.P. 2l0.5-212 C. (corr.), [a] =+10.1 1% in chloroform).

Analysis.-Calcd. for C H O C, 73.30; H, 8.95. Found: C, 73.56; H, 8.82.

Example 9 D-homopregnan-J7afi-ol-3J1,20-trione [III; X and X are 0, R"is H1 .-Chromic oxide (8.0 g.) was added in four portions to 100 ml. ofpyridine with stirring at 10 C. The solution was stirred for ten minutesat 10 C. and then for an additional ten minutes at room temperature.There was then added 8.757 g. ofD-homopregnane-3a,17a;8-dio1-11,20-dione dissolved in 70 ml. ofpyridine, and the mixture was stirred for one and one half hours at roomtemperature and allowed to stand for about fifteen hours. The reactionmixture was then diluted with water and then extracted with a 1:1.etherethyl acetate mixture. The extracts were Washed with dilutesulfuric acid and dilute sodium bicarbonate solution, dried overanhydrous sodium sulfate and concentrated. The residue, 8.36 g., M. P.173-178 C., was recrystallized first from an ethyl acetate-petroleumether (Skellysolve C) mixture and then from ethyl acetate and dried at110 C. in vacuo for eight hours, givingD-homopregnan-17afi-ol-3,11,20-trione, M. P. 1795-180 C. (corr.), [a]-=+36.5 (1% in chloroform).

Analysis.-Calcd. for C H O C, 73.30; H, 8.95. Found: C, 73.39; H, 8.99.

D-homopregnan-17ap-o1-3,11,20-trione was found to '10 possessprogesterone antagonizing properties as determined by the methoddescribed in Example 7.

Example 10 3ot-acet0xy-D-h0m0 1 7 (17a) pregnene 11,20 dione UV, X is O--OOOCHa X isO].-3a-acetoxy-17a-ethynyl-D-homoetiocholanl7a/3-ol-l1--one (5.0 g.) wasdissolved in 175 ml. of ethylene glycol by heating. Mercuric acetate(2.5 g.) was then added, the mixture was cooled to room temperature, 5.0ml. of 47% boron trifluoride-ether complex was added, and the mixturewas kept at room temperature for eighteen hours. Glacial acetic acid(150 ml.) was then added, and the mixture was stirred for eight hours atroom temperature and heated on a steam bath for five hours. The reactionmixture was added to two liters of water, extracted twice with methylenedichloride, and the extracts were washed with water and sodiumbicarbonate solution and concentrated. The residue was refluxed with 50g. of potassium carbonate in 400 ml. of methanol and ml. of water forone and one-half hours. The methanol was removed in vacuo, the residuediluted to 700 ml. with water, and the solid material was collected byfiltration and dried at 70 C., giving 4.2 g. ofD-homo-17(l7a)-pregnen-3a-ol-l1,20-dione. The latter was acetylated with30 ml. of acetic anhydride and 20 ml. of pyridine by heating forforty-five minutes on a steam bath. The reaction mixture was added to800 ml. of ice-water, the product was extracted with methylenedichloride, and the extracts were washed with dilute hydrochloric acidand sodium bicarbonate solution, dried over anhydrous sodium sulfate andconcentrated. The product was dissolved in 80 ml. of ether and 720 ml.of petroleum ether (Skellysolve A) and chromatographed on a column of250 g. of silicon dioxide. The column was eluted with ether-petroleumether mixtures containing gradually increasing amounts of ether. Thematerial eluted with 40% ether (2.0 g., M. P. 173l85 C.) wasrecrystallized successively from methanol, ethyl acetate-petroleum ether(Skellysolve C), benzene-petroleum ether (Skellysolve B), and ethylacetate, and dried at C. in vacuo for eight hours, giving 3a--acetoxy-Dhomo-17(17a)-pregnene-11,20-dione, M. P. 191193.5 C. (corr.), [a]=+149.8 (1% in chloroform).

Analysis-Calcd. for C I-1 0 C, 74.56; H, 8.87. Found: C, 74.64; H, 8.75.

Example 12 3a-acefoxy-D-h0mopregnane-Z1,20-di0ne [V; X is X is O]3rx-acetoxy-Dhomo-17,l7a-pregnene-l1,20-

dione (2.545 g., M. P. 183186 C.) in 200 m1. of absolute ethanol washydrogenated in the presence of 1.00 g. of 22% palladiumhydroxide-on-strontium carbonate catalyst at room temperature and 40lbs. per sq. inch pressure. Reduction was complete in about twenty-fiveminutes and the reaction mixture was filtered and concentrated. Theresidue (2.50 g., M. P. 169-180 C.) was recrystallized successively froman ethyl acetate-petroleum ether (Skellysolve C) mixture, methanol andacetone, giving 3a-acetoxy-D-homopregnane-l1,20-dione, M. P. 192.5-193.5C. (corn), [a] =-}-92.4 (1% in chloroform).

Analysis.-Cald. for (2241 13 04: C, H, 9.34. Found: C, 73.80; H, 9.28.

Example 13 3a-acetoxy-D-homopregnane-17a,8,20-di0l-1Lone [V H; R is CHCO, X is O].To a solution of 3.252 g. of3fi-acetoxy-D-homopregnan-l7ap-ol-11,20-dione EVI; R" is CH CO, X is 0](Example 1') in 100 ml. of methanol at 20 C. was added 0.304 g. ofsodium borohydride in 4 ml. of water. After one and one-half hours atroom temperature, 3 ml. of acetic acid was slowly added and the methanolwas removed in vacuo. The residue was diluted with water and the solidproduct was collected by filtration and dried, giving 3.172 g., M. P.257-264 C. The latter was recrystallized first from ethyl acetate andthen from methanol and dried at 115 C. in vacuo for eight hours, giving3a-acetoxy-D-homopregnane-17aB,20-diol-1l-one, M P. 262-273.5 C. (corn),[a] =+36.l (1% in chloroform) A nalysis.-'Calcd. for C H O C, 70.90; H,9.42. Found: C, 71.00; H, 9.35.

If in the above procedure sodium borohydride is replaced by twoequivalents of lithium aluminum hydride, there can be obtained3ot-acetoxy-D-homopregnane-11B,- 17a{3,20-triol [VIE R" is OHQGO, X is H1 Example 14 D-homopregnanedog] 1 {3,1 7a,8,20-tetr0l A mixture of 364mg. of 3a-acetoxy-D-homopregnane- 17afl,20-diol-11-one (Example 13), 350mg. of sodium borohydride, and 4 m1. of 35% aqueous sodium hydroxidesolution in 50 ml. of methanol was refluxed for 18 hours. The volatilematerial was removed in vacuo, the residue stirred with water, and thesolid product was collected by filtration, washed with water and driedat 70 C. After two recrystallizations from methanol and drying on avacuum oven at 110C. for eight hours, there was obtainedD-homopregnane-3a,l1,3,17a5,20 tetrol, M. P. 203208 C. (corn).

Analysis.-Calcd. for C H O C, 72.09; H, 10.45- Found: C, 72.26; H,10.38.

Example 15 D-homopregnane- SaJ7a,B,Z0-tri0l-1I-one [VII; R" is H, X isO] was prepared from 7.172 g. of D-homopregnane-3a,l7aB-diol-11,20-dione(Example 7) and 3.755 g. of sodium borohydride according to themanipulative procedure described above in Example 13. The crude product(7.163 g., M. P. 185-188 C.) was recrystallized first from ethanol andthen from ethyl acetate and dried at 120 C. in vacuo for eight hours,giving D-homopregnane-Sa,17a,6,20-triol-l1-one, M. P. 20 1.5207.5 C.(corn), [a] =+14.4 (1% in chloroform).

Analysis.Calcd. for C H O C, 72.49; H, 9.96. Found: C, 72.80; H, 10.22.

Dhomopregnane-Ea,17a,8,20-triol-l l-one was found to have progresteroneantagonizing propertiesas determined by the method described inExample7.

12 Example 16 3a,20-a'iacet0xy-D-h0m0pregnan-1 7aB-ol- 11- 0ne. -Thecombined mother liquors from the recrystallization of the productsdescribed above in Examples 13 and 15 were concentrated in vacuo. Theresidue was dissolved in acetone and again concentrated to removeresidual methanol. The residue was heated with 50 ml. of aceticanhydride and 30 ml. of pyridine for one hour on a steam bath. Thereaction mixture was poured into 850 ml. of water, and after one hourthe solid material was collected by filtration, recrystallized firstfrom an ethyl acetate-petroleum ether (Skellysolve C) mixture and thenfrom methanol and dried at C. in vacuo for eight hours, giving3a,20-diacetoxy-D-homopregnan-17aB-ol-l1- one, M. P. 1905-1925 C.(corr.), [a] =+16.9 (1% in chloroform).

Analysis.Calcd. for C H O C, 69.61; H, 8.99. Found: C, 69.63; H, 8.83.

Example 17 3wacetoxy-D-homopregnane-l 1,20-a'ione [V; X is X is O].Amixture of 3.30 g. of 3a,20-diacetoxy-D- homopregnan-l7afl-old l-one(Example 16) and 75 g. of zinc dust was heated in refluxing p-cymene (B.P. 174-l75 C.) with stirring for 42 hours. The reaction mixture wascooled and filtered, the zinc pad was washed through with ethyl acetateand the washings combined with the filtrate. The filtrate was steamdistilled until no more oil (p-cymene) appeared in the distillate. Theundistilled fraction was extracted with ethyl acetate, and the extractswere dried over anhydrous sodium sulfate and concentrated. The residue(3.09 g.) was dissolved in npentane containing 10% of ether and thesolution'was chromatographed on a column of g. of silicon dioxide. Thecolumn was eluted with ether-n-pentane'mixtures of gradually increasingether content. The material brought out by 60% ether was recrystallizedfrom an ethyl acetate-petroleum ether (Skellysolve C) mixture and therecrystallized material washed with n-hexane. The product thus obtainedwas recrystallized from a small volume of methanol and dried at 70,giving 3a-acetoxy- D-homopregnane-l1,20-dione, M. P. 1.91.5-1925 Itshowed no depression in melting point when mixed with a sample of theproduct obtained in Example 12, M. P. 192.5-193.5 C. A mixture of theproduct with the starting material, M. P. 190.5-192.5 C. had a sharplydepressed melting point, 158-171" C. 3

Example 18 21 -br0mo D h0m0pregnane-3a,1 7afl-diol-1 1,20-di0ne EIX; R"is H, X is O, R is OH, Hal is Br]. A solution of 23.56 g. ofD-homopregnane-3a,17afi-diol-11,20-dione in 250 ml. of glacial aceticacid was warmed to 35 C., and 1 ml. of a solution of 3.75 ml. of brominein 50 ml. of acetic acid was added. The solution was stirred until thebromine color faded, then the rest of the bromine solution was addeddropwise rather rapidly over a period of one hour and fifteen minutes.The reaction mixture was stirred for ten minutes longer, diluted to 3.5liters with water, and the solid product was collected by filtration anddried. The latter was recrystallized twice from 50 ml. of methanol andthen from an equal volume mixture of ethyl acetate and petroleum ether(Skeliysolve C) and dried at 60 C. in vacuo for eight hours, giving21-bromo-D-homopregnane-3a,17a,8-diol-l1,20-dioue, M. P. 200-202.5 C.(dec.) (corn), [a] =+25.7 (1% in chloroform) Analysisr Calcd. for C HBrO C, 59.86; H, 7.54; Br, 18.11. Found: C, 59.60; H, 7.35; Br, 18.28.

Example 19 (a) 21-bromo-Dh0m0pregnane-3a,17afi diol 11,20-

dione [IX; R is H, X' is O, R is OH, Hal is Br] was prepared from 4.24g. of D-homopregnane-3a,17a;3-diol- 11,20-dione and 56 ml. of 0.2205 Mbromine in chloroform according to the manipulative procedure describedabove in Example 18 except that 100 ml. of chloroform was used as thesolvent instead of acetic acid. The reaction mixture was washed withsodium bicarbonate solution, dried over anhydrous sodium sulfate andconcentrated. The residue was recrystallized from acetone giving 4.157g. of 21-bromo-D-homopregnane-3a,17ap-diol- 11,20-dione.

(b) 21-br0mo-D-h0m0pregnan-I7a;8-0l-3,11,20 trione [X; X is O, R is OH,Hal is Br].The 2l-bromo-D- homopregnane-3a,17afi-diol-11,20-dioneobtained above in part (a) was dissolved in 250 ml. of tertiarybutylalcohol, cooled to 10 C., and 5 ml. of methanol and 0.8 ml. of 30%hydrogen bromide in acetic acid were added. To this solution there wasadded 2.2 g. of N-bromoacetamide, and the reaction mixture was mixedwell and allowed to stand at 5-8 C. for five hours. The reaction mixturewas diluted with water, extracted with methylene dichloride, and theextracts were washed with water and with sodium bicarbonate solution,dried over sodium sulfate and concentrated. There was thus obtained21-bromo-D-homopregnan-17a,8-ol-3,11,20-trione, M. P. 2317- 238 C.(dec.) (uncorr.) when immersed at 220 C.

Example 20 21-acet0xy-D-homopregnan-17a 8 ol 3,11,20-tri0ne [XI; X is O,R is OH, R is COCH l.--A mixture of the2l-bromo-D-homopregnan-17afl-ol-3,11,20-trione obtained above in Example19, 8.0 g. of potassium bicarbonate, 4.8 ml. of glacial acetic acid and120 ml. of acetone was refluxedjand stirred for twenty-three hours. Thereaction mixture was diluted with water, the acetone was removed invacuo, the residual aqueous mixture was extracted with methylenedichloroide, and the extracts washed with water, dried over anhydroussodium sulfate and concentrated. The residue was dissolved in 800 ml. ofn-pentane containing of ether and chromatographed on a column of 300 g.of silicon dioxide. The column was eluted with ether-n-pentane mixturescontaining increasing proportions of ether. 100% ether brought out thecrystalline product, M. P. 182-184 C. The latter was recrystallizedfirst from a 1:3 ethyl acetate petroleum ether (Skellysolve B) mixtureand then from dilute methanol and dried at 70 C., giving 1.3 g. of 21-acetoxy-D-homopregnan-17afi-ol-3,11,20trione, M. P. 191-193 C. A samplewhen recrystallized from dilute methanol and dried at 110 C. in vacuofor eight hours had the M. P. 193.5-196 C. (corn), [o:.] =+1.3 (1% inchloroform),

Analysis.-Calcd. for C H O C, 68.87; H, 8.19. Found: C, 68.60; H, 8.45.1

Example 21 (a) 21-br0mo-D-homopregnane-3a,1 7aa-diol-1I,20-dione [IX; R"is H, X is O, R is OH, Hal is Br] was prepared from 5.82 g. ofD-homopregnane-3a,17aa-diol- 11,20-dione and 77 ml. of 0.2205 M brominein chloroform according to the manipulative procedure described above inExample 19, part (a). The product was used in the next step withoutpurification.

(b) 21 -br0m0-D-h0m0pregnan-1 7aa-0l-3J 1 ,20-tri0ne [X; X is O, R isOH, Hal is Br] was prepared from the crude2l-bromo-D-homopregnane-3a,17aa-diol-11, 20-dione, obtained above inpart (a), and 2.34 g. of N- bromoacetamide according to the manipulativeprocedure described above in Example 19, part (b). The crude product wasused in the next step without purification.

(c) 21-acet0xy-D-homopregnan-I7aa-ol-3,I1,20-tri0ne [XI; X is 0, R isOH, R" is COCH was prepared from thecrude'2-1-bromo-D-homopregnan-17aa-ol-3,11, 20-trione, obtained above inpart (b), 8 g. of potassium bicarbonate, 4.8 ml. of glacial acetic acidand 115 ml.

. had the M. P. 199-2015 C. (corn), with resolidification at 205 C. andremelting at 223 C. [a] =+63.8 (1% in chloroform).

Analysis.-Calcd. for C H O C, 68.87; H, 8.19. Found: C, 68.60; H, 8.38.

(corn) Example 22 4 bromo D homopregnan-I7afi-0l-3,1],20-tri0ne.- Asolution was prepared from 19.385 g. ofD-homopregnan-17a/i-ol-3,11,20-trione in 200 ml. of glacial acetic acidcontaining four drops of 35% hydrogen bromide in acetic acid. A secondsolution was prepared from 19.90 g. of pyridinium bromide perbromide and7.21 g. of sodium acetate trihydrate in 1.25 ml. of glacial acetic acid.The second solution was added drop-- wise to the first solution. Afteraddition was complete, the reaction mixture was diluted with water,extracted three times with methylene dichloride, and the extracts werewashed with water and sodium carbonate solution, dried over anhydroussodium sulfate, concentrated to a m1. volume and diluted with 150 ml. ofabsolute ether. After cooling in ice, the crystalline productprecipitated and was collected by filtration and recrystallized bydissolving in acetone, concentrating and adding ether. There was'thusobtained 18.22 g. of 4-bromo-D-homopregnan-l7a,B-ol-3,11,20-trione, M.P. 200-206 C. (dec.) when immersed at 195 C. A sample whenrecrystallized from acetone had [a] =+71.4 (1% in chloroform).

Analysis.-Calcd. for C H BrO C, 60.1.3; H, 7.11; Br. 18.19. Found: C,60.40; H, 7.28; Br, 18.10.

Example 23 D homo 4 pregnan J7apl ol 3,11,20 trione.- 4 bromo Dhomopregnan 17a,8 o1 3,11,20 trione (15.97 g.) was dissolved in ml. offreshly distilled dimethylfo-rmamide, and dry nitrogen gas was passedover the surface with stirring for fifteen minutes. Anhydrous lithiumchloride (4.64 g.) was then added, and the mixture was heated for twohours at 98 C. with stirring. The reaction mixture was cooled, dilutedto two liters with ice-water, mixed well, and the solid product wascollected by filtration, giving 11.04 g., M. P. 171201 C. The latter wasrecrystallized first from acetone and then twice from ethyl acetate,giving D-horno-4-pregnen- 17afi-ol-3,11,20-trione, M. P. 221-2265 C.-(corr.), [a] =+172.2 (1% in chloroform).

Analysis.Calcd. for C H O C, 73.71; H, 8.44. Found: C, 73.46; H, 8.62.

D-homo-4-pregnen-17a 8-ol-3,l1,20-trione was found to have testosteroneantagonizing properties, determined by measuring the counteractinginfluence upon the effect of testosterone ontbe seminal vesicle in therat.

Example 24 21 acetoxy D-homopregnane-MJ7a;3-di0l-11,20-zlione.-A mixtureof 4.41 g. of 21-bromo-D-homopregmane-3a,l7aB-diol-11,20-dione, 5.0 g.of potassium bicarbonate, 3.0 ml. of glacial acetic acid, 70 ml. ofacetone and 0.05 g. of sodium iodide was refluxed with stirring fornineteen hours. The reaction mixture was diluted with water, the acetonewas removed in vacuo, the residual aqueous mixture was extracted withchloroform, and the extracts were washed. with water, dried overanhydrous sodium sulfate and concentrated. The residue was dissolved inacetone, the solution was filtered, the filtrate concentrated to a smallvolume and the product induced to crystallize by adding n-heptane. Theproduct was recrystallized twice from an ethyl acetate-petroleum ether(Skellysolve C) mixture, giving 21-acetoxy-D-homopregnane-3u,17a,8-diol-11,20-dione, M. P. 207209 C. (uncorr.).

Example 25 (a) 4-br0m0-21-acet0xy-DJwmopregnan-l 7a5-0l-3,11, ZO-trioneEXII; Hal is Br, X is O, R is OH, R" is COCH ].21 acetoxy Dhomopregnan-17a 8-ol-3,11, 20-trione (1.076 g.) was dissolved in 15 ml.of glacial acetic acid containing two drops of hydrogen bromide inacetic acid. To this solution there was added drop- Wise with stirring asolution of 975 mg. of pyridinium bromide perbromide and 340 mg. ofsodium acetate trihydrate in 10 ml. of glacial acetic acid. The additionwas carried out at such a rate that each drop was allowed to decolorizebefore adding the next. The reaction mixture was then stirred for fiveminutes, diluted with water and extracted with methylene dichloride. Themethylene dichloride extracts were washed with water and sodiumbicarbonate, dried over anhydrous sodium sulfonate and concentrated. Thecrude 4-bromo-21-acetoxy-D-homopregnan-l7a 8-ol-3-l1,20-trione thusobtained was used directly in the next step.

(b) 21-acet0xy-D-homo-4-pregnen-17afl-ol-3,1 1,20-trione EXIII; X is O,R is OH, R" is COCH ].The crude 4 bromo 21acetoxy-17a/3-ol-3,11,20-trione obtained above in part (a) was treatedwith 326 mg. of anhydrous lithium chloride in 25 ml. of freshlydistilled dimethylformamide according to the manipulative proceduredescribed above in Example 23. The crude product was extracted withmethylene dichloride, and the extracts were concentrated, giving about 1g. of 21- acetoxy-D-homo-4-pregnen-17a,B-ol-3 ,11,20-trione.

By an analogous procedure,21-acetoxy-D-homopregnan-17aa-ol-3,11,20-trione can be converted toZI-acetoxy-D-homo-4-pregnen-17aa-ol-3,11,20-trione.

I claim:

1. A compound selected from the group consisting of: (A) compounds ofthe etiocholane series having the formula wherein X=, X: and X" areselected from the class consisting of R is selected from the classconsisting of H, OH and OAcyl, and R is selected from the classconsisting of H, OH, OAcyl, chlorine, bromine and iodine, Acyl in allcases being selected from the group consisting of loweralkanoyl,carboxy-lower-alkanoyl and monocarbocyclic aroyl groups; (B) compoundsof the etiocholane series of the above formula in which a hydrogen atomat position 17 and the group R at position 17a are eliminated thushaving a double bond in the 17,17a-p0sition; and (C) compounds of theetiocholane series of the above formula having a halogen atom selectedfrom the group consisting of chlorine, bromine and iodine in place ofone of the hydrogen atoms at position 4, X being 0.

and

2. A compound of the etiocholane serieshaving the formula wherein Acylis a member of the group consisting of lower-alkanoyl,carboxy-loWer-alkanoyl and monocarbocyclic aroyl groups.

3. A compound of the etiocholane series having the formula 4. A compoundof the etiocholane series having the formula 6. A compound of theetiocholane series having the formula AcylO wherein Acyl is a member ofthe group consisting of lower-alkanoyl, carboxy-lower-alkanoyl andmonocarbs sl s e yl stews 7 1s 7. A compound of the etioeholane serieshaving the 12. A compound of the etiocholane series having the formulaformula cm om CH1 5 CHI HOE error; ---on OH 0H: CH3

omcoo HO 13.15 dfth tihlan '111' e 8. A compound of the etiocholaneseries having the formula compoun o e e 0c 0 6 th formula on a CH: 0 H10C o CH HOH 0H 0H 0 011, CH;

9. A compound of the etiocholane series having the wherem Hal 1s ahalogen atom selected from the group formula consisting of chlorine,bromine and iodine.

14. A compound of the etiocholane series having the formula omrm =0 on"CHI 0111000 wherein Hal is a member of the group consisting ofch1obromine and lodlm- 15. A compound of the etiocholane series havingthe 10. A compound of the etlocholane series having the f ula formula onI CH; 0E,

CHIBI. =0

=0 -OH 0 o CH! OH) HO H0 0 16. A compound of the etiocholane serieshaving the 11. A compound of the etiocholane series having the formulaformula 0H,

CH CH 05 CHnOCOOHr o 031000 J (References on following page) UNITEDSTATES PATENT OFFICE Certificate of Correction Patent No. 2,860,158November 11, 1958 Raymond 0. Clinton It is hereby certified that errorappears in the printed specification of the above numbered patentrequiring correction and that the said Letters Patent should read ascorrected below.

Column 6, line 48, for eluated read eluted; column 7, line 24, for"3,17aflread 3a,17a,B--; column 10, line 10, for 17a-ethyny1- read-l7aa-ethynyl--; column 11, line 18, for 3,B-acetoxyread 3a-acetoxyline74, for progresterone read progesterone-; column 12, line 15, for [a]read -[a] line 41, for 60% read 50%-; column 14, line 414;, for4-pregnan read --4-pregnen- Signed and sealed this 7th day of April1959.

Attest: KARL H. AXLINE, ROBERT C. WATSON, Attesting Ofioer. Uomzaeionerof Patents.

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF: (A) COMPOUNDS OFTHE ETIOCHOLANE SERIES HAVING THE FORMULA